Phase 2b Clinical Study Evaluating Efficacy and Safety of TAR-200 in Combination with Cetrelimab, TAR-200 Alone, or Cetrelimab Alone in Participants with High-Risk Non-Muscle Invasive Bladder Cancer (NMIBC) Unresponsive to Intravesical Bacillus Calmette-Guerin (BCG) who are Ineligible for or Elected Not to Undergo Radical Cystectomy

1. Age >=18 years male or female (or the legal age of consent in the
jurisdiction in which the study is taking place) at the time of informed
consent 2. Histologically confirmed diagnosis of persistent or recurrent CIS
(or Tis), with or without papillary disease (T1, high-grade Ta) or papillary
disease only (high-grade Ta or any T1 and absence of CIS), within 12 months of
completion (last dose) of adequate BCG therapy, in patients who have received
adequate BCG 3. All visible papillary disease must be fully resected (absent)
prior to randomization (residual CIS acceptable for participants eligible for
Cohorts 1, 2, and 3 only) and documented in the eCRF at Screening cystoscopy.
For patients with papillary disease only (Cohort 4), local urine cytology at
screening must be negative or atypical (for HGUC). 4. Participants must be
willing to undergo all study procedures (e.g., multiple cystoscopies from
Screening through the end of study and TURBT/bladder biopsy for assessment of
recurrence/progression) 5. Participants must be ineligible for or have elected
not to undergo radical cystectomy 6. BCG-unresponsive high-risk NMIBC after
treatment with adequate BCG therapy defined as a minimum of 5 of 6 full doses
of an induction course (adequate induction) plus 2 of 3 doses of a maintenance
course, or at least 2 of 6 doses of a second induction course 7. All AEs
adverse events associated with any prior surgery and/or intravesical therapy
must have resolved to CTCAE version 5.0 Grade <2 prior to screening 8.
Participants must sign the informed consent form ICF indicating that he or she
understands the purpose of, and procedures required for, the study and is
willing to participate in the study and agree to store samples when applicable
9. Eastern Cooperative Oncology Group ECOG performance status Grade 0, 1, or 2
10. Adequate bone marrow, liver, and renal function (creatinine clearance >30
mL/min) 11. Contraceptive use by participants should be consistent with local
regulations regarding the use of contraceptive methods for participants
participating in clinical studies. Investigators will advise both male and
female participants on the options for banking of sperm and ova, respectively
for reproductive conservation a. A female participant must be either of the
following: i. Not of childbearing potential ii. Of childbearing potential and
practicing true abstinence, or have a sole partner who is vasectomized, or
practicing at least 1 highly effective user independent method of contraception
Participant must agree to continue the above throughout the study and for 6
months after the last dose of study treatment. Note: If a women becomes of
childbearing potential after start of the study, the woman must comply with
point ii, as described above. A female participant must also agree to not
donate eggs (ova, oocytes) or freeze for future use for the purposes of
assisted reproduction during the study and for at least 6 months after the last
dose of study drug, and not be breastfeeding (including participants
temporarily withholding breastfeeding) and not planning to become pregnant
during the study and for at least 6 months after the last dose of study drug.
Female participants should consider preservation of eggs prior to study
treatment as anti-cancer treatments may impair fertility. Investigators will
advise female participants on the options of banking of ova for reproductive
conservation. b. A male participant must wear a condom (with or without
spermicidal foam/gel/film/cream/suppository) when engaging in any activity that
allows for passage of ejaculate to another person during the study and for a
minimum of 6 months after receiving the last dose of study treatment. His
female partner, if of childbearing potential, must also be practicing a highly
effective method of contraception. If the male participant is vasectomized, he
still must wear a condom (with or without spermicidal
foam/gel/film/cream/suppository), but his female partner is not required to use
contraception. Male participants should consider preservation of sperm prior to
study treatment as anticancer treatments may impair fertility. Investigators
will advise male participants on the options for banking of sperm for
reproductive conservation. A male participant must also agree to not donate
sperm for the purpose of reproduction during the study and for at least 6
months after the last dose of study drug, and not plan to father a child while
enrolled in this study or within 6 months after the last dose of study drug 12.
A female participant of childbearing potential must have a negative serum test
at screening and a negative urine test within 72hours of the first dose of
study treatment and must agree to further serum or urine pregnancy tests during
the study, that may exceed those listed in the Schedule of Activities 13.
Participants must be willing and able to adhere to the lifestyle restrictions
specified in this protocol

1. Presence or history of histologically confirmed, muscle-invasive, locally
advanced, nonresectable, or metastatic urothelial carcinoma (ie,T2,T3,T4,
and/or Stage IV).
2. Must not have had urothelial carcinoma or histological variant at any site
outside of the urinary bladder. Ta/T1/CIS of the upper urinary tract (including
renal pelvis and ureter) is allowable if treated with complete
nephrouretrectomy more than 24 months prior to randomization.
3. Active malignancies (ie progressing or requiring treatment change in the
last 24 months prior to randomization) other than the disease being treated
under study:
a. skin cancer (non-melanoma or melanoma) that is considered completely cured
b. non-invasive cervical cancer that is considered completely cured
c. adequately treated lobular carcinoma in situ (LCIS) and ductal CIS
d. history of localized breast cancer and receiving antihormonal agents
e. history of localized prostate cancer (N0M0) and receiving androgen
deprivation therapy
f. Localized prostate cancer (N0M0)
4. Presence of any bladder or urethral anatomic feature (eg. urethral
stricture) that may prevent the safe insertion, indwelling use, or removal of
TAR-200, or passage of a urethral catheter for intravesical chemotherapy, or
administration of intravesical BCG. Participants with tumors involving the
prostatic urethra in men will be excluded.
5. Evidence of bladder perforation during diagnostic cystoscopy.
6. Bladder post-void residual (PVR) volume >350mL at Screening after second
voided urine.
7. No history of acute ischemic heart disease within 30 days of cohort
assignment, or history of uncontrolled cardiovascular disease.
8. A history of clinically significant polyuria with recorded 24-hour urine
volumes greater than 4000 mL.
9. Received a live virus vaccine within 30 days of planned start of study
treatment. Inactivated (non-live or non-replicating) vaccines approved or
authorized for emergency use (eg, COVID-19) by local health authorities are
allowed.
10. Active infection requiring systemic IV therapy within 14 days prior to
randomization.
11. Currently participating or has participated in a study of an
investigational agent and received study therapy or investigational device
within 4 weeks prior to screening.
12. Indwelling catheters are not permitted; however, intermittent
catheterization is acceptable.
13. Received serial intervening intravesical chemotherapy or immunotherapy from
the time of pre-screening or screening cystoscopy/TURBT to starting study
treatment. Peri-operative intravesical chemotherapy prior to study is allowed
per institutional guidelines.
14. Prior therapy with an anti-programmed -cell death 1, anti-PD-ligand 2
agent, or with an agent directed to another co-inhibitory T-cell receptor.
15. Not recovered from toxicity of prior anticancer therapy (except toxicities
which are not clinically significant such as alopecia, skin discoloration).
16. No clinically significant liver disease that precludes participant
treatment regimens prescribed on the study.
17. Human immunodeficiency virus (HIV) infection, unless the participant has
been on a stable anti-retroviral therapy regimen for the last 6 months or more
prior to randomization and has had no opportunistic infections and a CD4 count
of >350 in the last 6 months.
18. Active hepatitis B or C infection (for example, participants with history
of hepatitis C infection but undetectable hepatitis C virus PCR test and
participants with history of hepatitis B infection with positive HBsAg antibody
and undetectable PCR are allowed).
19. Concurrent urinary tract infection, defined as a symptomatic infection with
a positive urine culture with a bacterial count of >=10^5 colony forming units
(CFU)/mL in urine voided from women, or >10^4 CFU/mL in urine voided from men,
or in straight-catheter urine from women.
20. Known hypersensitivity to gemcitabine (or other drug excipients) or
chemically-related drugs.
21. Known hypersensitivity to the TAR-200 device constituent or the (TAR-200)
UPC materials.
22. Evidence of radiographic features associated with pulmonary
fibrosis/advanced interstitial lung disease or active non-infectious pneumonitis
23. Participants must not have active tuberculosis.
24. Major surgery within 4 weeks before screening (TURBT is not considered
major surgery).
25. Any condition for which participation would not be in the best interest of
the participants or that could prevent, limit, or confound the
protocol-specified assessments.